tbuckley/cabot-search huggingface dataset:
PB2199: A REAL WORLD STUDY OF PEG-RHG-CSF ON HEMATOPOIETIC RECOVERY AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: J. Xu, F. Kong, S. Cui, K. Liu, Z. Liu, J. Wang, W. Zheng, Y. Zhou, R. Xu
Journal: HemaSphere (2022)

Background: The data of PEG-rhG-CSF on hematopoietic recovery after allogeneic hematopoietic stem cell transplantation is few in China. Aims: To observe the efficacy and safety of PEG-rhG-CSF on hematopoietic recovery after allogeneic hematopoietic stem cell transplantation（allo-HSCT）in the real world study. Methods: 103 patients after allo-HSCT were enrolled in this study from January 2019 to October 2021. PEG-rhG-CSF(xinruibai) was used in the hematopoietic recovery and given in the dose of 100μg/kg on day +1and day +8. Hematopoietic stem cell implantation time and recovery of white blood cells (WBC) and platelet (PLT)，implantable syndrome and Infectious fever were observed until day +60. The patients were divided into Aplastic Anemia group and hematological malignancy group for further study. Results: All patients got neutrophil implantation successfully and the median neutrophil implantation time was 12 (7-25) d. 3 patients were failed to complete platelet implantation and the platelet implantation rate is 97%. The median platelet implantation time of the other 101 evaluable patients was 17 (10-47) d. The incidence of implantable syndrome and infection was low and there was no related death case. There were no significant differences of the neutrophil implantation time［11.5（7-25）d vs 12（9-23）d，P＞0.05］and platelet implantation time［17.5（10-43）d vs 17（11-47）d，P＞0.05］between Aplastic Anemia and hematological malignancy groups respectively. There was no significant difference in the incidence of fever and duration of fever between two groups(P＞0.05)． Summary/Conclusion: The efficacy of PEG-rhG-CSF in promoting hematopoietic recovery after allogeneic hematopoietic stem cell transplantation is good, without severe untoward effects. There is no obvious difference in hematopoietic recovery in Aplastic Anemia and hematological malignancy.
Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response
Authors: Zhengnan Yuan, Ladie Kimberly De La Cruz, Xiaoxiao Yang, Binghe Wang
Journal: Pharmacological Reviews (2022)

Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high <i>μ</i>M. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics. <h3>Significance Statement</h3> The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.
Abstract SY42-01: Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche
Authors: Linheng Li
Journal: Cancer Research (2022)

Abstract Tumor-initiating stem cells shape microenvironment into an immunosuppressive barrier and a pro-tumorigenic nicheLinheng Li Stowers Institute for Medical Research, Kansas City MO 64110Kansas University of Cancer Center, Kansas City KS 66160 Accumulated evidence supports the concept that tumor-initiating stem cells (TSCs) are at the root of tumor/cancer and are largely responsible for the commonly observed resistance to chemoradiotherapy (CRT) and frequent relapse of disease. How a subset of TSCs, or therapy resistant TSC (TrTSC), survives and supports tumor regrowth post treatment is a fundamental biological question and clinically unsolved problem. Recently, we utilized single-cell RNA-sequencing to identify therapy resistant TSCs (or TrTSCs) in mouse models of CRT-challenged intestinal adenoma, followed by bioinformatics analysis to reveal the bidirectional crosstalk that occurs between TSCs and the tumor microenvironment (TME). The results of the analysis indicate that TSCs shape the TME into an immunosuppressive barrier. Particularly, TrTSCs recruit tumor-associated monocytes and macrophages (TAMMs), which in turn, via Cox-2 dependent prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, induce Akt-mediated phosphorylation of β-catenin and thus enhance the β-catenin activity. Furthermore, we show that enhanced β-catenin signaling upregulates multiple immune-checkpoint genes, thus empowering the immune escape capabilities of TSCs. Taken together, overcoming both the extrinsic immunosuppressive barrier and intrinsic immune escape has the potential to increase the efficacy of checkpoint inhibition therapies against cancers in the future. Citation Format: Linheng Li. Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY42-01.
P1428: IMPLICATIONS OF THE RUXOLITINIB (JAK1/JAK2 INHIBITOR) ON GRAFT-VERSUS-LEUKAEMIA EFFECT MEDIATED BY THE NK CELL.
Authors: C. Durán, C. Martín Cortázar, C. Ferreras, A. Navarro Zapata, L. Clares Villa, K. Al-akioui, A. Escuredo, A. Pernas, V. Galán, D. Bueno, L. Sisinni, A. Pérez Martínez
Journal: HemaSphere (2022)

Background: Haematopoietic stem cell transplantation (HSCT) is one of the therapeutic options for high-risk paediatric leukaemia. One of the adverse effects of HSCT is graft-versus-host disease (GvHD). Ruxolitinib is one of the drugs used as GvHD treatment. In this context, alloreactive NK cells have been correlated with a lower relapse rate, decreasing GvHD with maintenance of beneficial graft-versus-leukaemia (GvL) effect. Aims: We aimed to evaluate the role of Ruxolitinib on the NK cell mediated GvL effect. Methods: Purified NK cells were obtained from healthy donors. NK cells were incubated for 16h with LPS and CpG in presence or absence of Ruxolitinib (0.1, 1, 10 µM). Their gene expression and production of pro-inflammatory cytokines IL-1β, TNFα, IFNγ and IL-6 were analysed by RT-qPCR and ELISA, respectively. Functional capacity was also assessed using DELFIA Cell Cytotoxicity Assay and CD107a degranulation assay against leukaemic cell lines by flow cytometry. To evaluate proliferative capacity, activated and expanded NK cells (NKAEs) were monitored in presence or absence of Ruxolitinib. Phosphorylation of STAT3 and STAT5 of JAK/STAT pathway was studied by western blot. Results: Stimulated NK cells treated with increasing doses of Ruxolitinib show decreased mRNA expression of TNFα, IFNγ and IL-6 in a dose-dependent manner. In terms of proinflammatory cytokine release, activated NK cells produce lower levels of pro-inflammatory cytokines (TNFα, IFNγ and IL-6) in the presence Ruxolitinib in a dose-dependent manner. The cytotoxic and degranulation capacity of stimulated NK cells was reduced in the presence of increasing doses of Ruxolitinib but not completely abolished, versus K562, SEM and MV-4-11 cell lines. Treatment with 1 and 10 uM Ruxolitinib impairs NKAES cell proliferation, while at low doses of Ruxolitinib NKAES cells proliferate until day 14. Ruxolitinib inhibits phosphorylation of the JAK/STAT pathway with no effect on Toll-Ligand Receptors signalling pathway (activated by LPS and CpG ligands). Summary/Conclusion: The JAK1/JAK2 inhibitor Ruxolitinib decreases functional and proliferative capacities of NK cells from healthy donor, inhibiting their GvL effect in vitro.
PB2195: MOBILIZATION WITH CYTARABINE AND GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) GIVES BETTER YIELD THAN MOBILIZATION WITH G-CSF ALONE OR COMBINED WITH CYCLOPHOSPHAMIDE
Authors: S. Simeonov, I. Tonev, V. Denchev, M. Stoichov, Y. Davidkova, E. Aleksov, T. Zhivkov, M. Stoyanova, M. Donchev, G. Arnaudov, M. Mincheff
Journal: HemaSphere (2022)

Background: Patients with multiple myeloma are poor mobilizers and often require multiple cytapheresis procedures. Most popular mobilization regimens are with G-CSF given as a sole treatment or in combination with cyclophosphamide. Recently, several reports indicated that higher yields could be obtained following chemomobilization with cytarabine and G-CSF. Aims: Our aim was to compate the effectiveness of chemomobilization with cytarabine and G-CSF with the other regimens which we have used. Methods: Patients received 2x400mg/m2 cytarabine for two days, followed by 5mcg/kg G-CSF two days after for at least nine days. Cytapheresis was initiated with WBC count above 5x109/L, PLT count above 30x109/L and CD34+ cell count above 20/µl. Results of this group of patients were compared with results from a historic group of myeloma patients harvested between 2018 and 2020. Results: The new regimen showed markedly higher initial counts of CD34+ cells resulting in significantly better average yields (12.6x10^6/kg for the cytarabine + G-CSF group; 3.98 x10^6/kg for the G-CSF group and 4.998 x10^6/kg for the Cyclophosphamide+ G-CSF group). Summary/Conclusion: Compared with other hematological malignancies, patients with multiple myeloma are hard to mobilize for collection of sufficient CD34+ cells. Possible explanations are advanced age and bone marrow involvement. Chemomobilization with cytarabine and G-CSF seem to overcome poor mobilization and collection yields for this patient group.
PB2339: PROJECTED LIFETIME ECONOMIC BURDEN OF TRANSFUSION DEPENDENT BETA-THALASSEMIA IN THE UNITED STATES
Authors: C. Udeze, K. Maruszczyk, M. Atter, A. Lopez
Journal: HemaSphere (2022)

Background: Beta-thalassemia is a rare hereditary blood disorder affecting approximately 2,000 individuals in the United States (US) and is characterized by reduced or absent beta globin production, leading to ineffective red blood cell production and anaemia. The most severe form of the disease is transfusion-dependent beta-thalassaemia (TDT), in which patients are dependent on regular red blood cell transfusions for survival. TDT patients suffer from chronic anaemia and the effects of iron overload despite chelation therapy, both of which result in significant morbidity and lead to premature mortality. The lifetime economic burden of TDT in the US is not well characterized. Aims: To estimate the per-patient lifetime direct healthcare cost of TDT from a US healthcare payer perspective using an economic model developed based on published model frameworks. Methods: An individual-level simulation model was used to estimate the lifetime direct healthcare costs for patients with TDT in the US. The model followed a cohort of TDT patients, who were assumed to receive an average of 16.8 blood transfusions per year, from birth until death. Like previously published economic models for TDT, mortality was estimated based on transfusion status and presence of TDT complications. Key complications tracked in the model included cardiac complications, liver complications, and endocrine complications (diabetes and hypogonadism). Cost of complications were derived from literature and the wholesale acquisition costs in the US were used to inform iron chelation therapy prices. Scenario analyses were conducted to determine the impact of lower iron chelation therapy costs (based on estimates from a published retrospective claims analysis) and average annual number of blood transfusions (12 and 20) on lifetime costs. The cost and impact of a recently approved non-curative TDT therapy, luspatercept, was not included in this analysis. Results: The model followed patients with TDT for an average of 39 years, over which time each patient incurred an average of 686 blood transfusions. The cost of TDT over the lifetime horizon was estimated to be $5.4 million. The majority of costs were for iron chelation therapy (68%, $3.7 million) and blood transfusions (30%, $1.6 million). Using the alternative cost inputs for iron chelation therapy (approximately 33% lower costs) lowered lifetime cost estimates to $4.2 million. Additional scenario analyses demonstrated the lifetime costs of TDT ranged from $5.0 million to $5.7 million when varying the average number of transfusions per year from 12 to 20. Summary/Conclusion: Model projections show significant lifetime economic burden with TDT in the US. Cost of chelation therapy and frequency of transfusions are the main drivers of modelled lifetime cost estimates. Treatments that can reduce the need for blood transfusions and iron chelation therapy in this population would significantly lower this economic burden.
PB2068: RETROSPECTIVE ANALYSIS OF HAIRY CELL LEUKEMIA (HCL) PATIENTS (PTS) TREATED WITH DIFFERENT MODALITIES AS FIRST LINE: REAL-LIFE EXPERIENCE OVER 20 YEARS IN KUWAIT.
Authors: A. Alhuraiji, M. Ram, A. Kunhikrishnan, S. Alshemmari, A. Hamadah, A. R. Shah, F. Khadadah, R. Pandita
Journal: HemaSphere (2022)

Background: Introduction: Hairy cell leukaemia (HCL) is a rare chronic lymphoproliferative disorder Aims: We retrospectively analysed all HCL cases diagnosed and treated at the Department of Hematology at Kuwait Cancer Control Center over a 20 year period. Methods: Baseline parameters collected included patient and disease demographics including bone marrow findings, as well as treatment protocols, and complications arising from treatment or relapse. Overall survival (OS) and progression free-survival (PFS) were calculated using a Kaplan-Meier analysis. Results: Forty-one patients with a median age of 51 (range 31–78) years were enrolled in the study over the time period 1994-2020. Diagnosis was established according to the WHO criteria for HCL. Clinical characteristics are shown in Table 1. Almost one third of the pts were Kuwaiti which reflects the demographic distribution of the country’s population. All pts were male (n=40) except for 1 pt. Treatment was initiated in 39 pts. In first-line, 28 pts were treated with cladribine (2CDA) alone, five received 2CDA in combination with rituximab, and four received interferon. The overall response rate (ORR) was 87.8%. In pts who received 2CDA-based therapy, the ORR was 97%. After a median follow-up of 92 months (3-266), median OS was not reached and median PFS was 7.7 years (95% CI, 5yrs-NR) (Figure 1). Sixteen pts (39%) had disease progression and were retreated mostly with 2CDA. Therapy was well tolerated with no reported treatment-related mortality. Febrile neutropenia was 22%. Image:Summary/Conclusion: This is the first report of HCL characteristics and outcomes from Kuwait. HCL pts have outcomes that are comparable to those in the published literature.
PB2174: ON THE ROBUSTNESS OF THE BUCCAL EPITHELIUM FOR ASSESSING RECIPIENT DNA PROFILE IN PATIENTS AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: N. Risinskaya, A. Yushkova, F. Shikhveledova, M. Drokov, L. Kuzmina, A. Sudarikov, E. Parovichnikova
Journal: HemaSphere (2022)

Background: Сommonly DNA from the buccal epithelium of patients is used to confirm the germinal nature of mutations, as well as the reference of the recipient DNA for monitoring chimerism after hematopoietic stem cell transplantation (HSCT). We came across the cases where mutation load calculated for DNA isolated from the buccal epithelium did not correspond to either the heterozygous or homozygous variant. In addition, we accidentally noticed in some patients after BMT a significant admixture of donor DNA in the samples isolated from the buccal epithelium. These facts prompted us to investigate post-transplant chimerism in the buccal epithelium. Aims: To evaluate the relevance of the buccal epithelium swab as a reliable source for a reference of the recipient DNA profile in patients after HSCT. Methods: The study included 63 patients admitted to the National Research Center for Hematology for allogeneic HSCT from 2007 to 2022, with complete donor chimerism in the blood. Buccal epithelium swab was taken an OLDANS plastic-viscose probe-tampon (Russia). Cells were suspended and lysed in 20 μl of buffer containing 0.5% NP40, 50 mM Tris (pH 8.3), 75 mM KCl, and 20 μg proteinase K. Short tandem repeats (STR) profiling was carried out by polymerase chain reaction using a lyophilized CorDIS Plus multiplex kit (19 polymorphic STR markers and the human amelogenin X\Y locus), followed by separation of PCR products by capillary electrophoresis. Chimerism was calculated based on the percentage of unique donor and recipient markers in informative STR loci using GeneMapper v.4-0 software. Results: Of 63 patients, only 14 (22%) had a 100% recipient STR profile in the buccal epithelium. Mixed donor-recipient chimerism was found in the buccal epithelium of 49 patients with the proportion of own recipient DNA ranging from 11% to 98%. A re-examination of the buccal epithelium was performed a month later for 12 patients. Of these, in three patients with previously mixed chimeras 100% recipient STR profile was detected. In two patients the balance in the mixed chimera shifted towards the recipient. One patient lost 100% recipient STR profile and become chimera with 43% of the recipient. In six cases, the balance of donor and recipient DNA in the buccal epithelium remained almost the same for two consecutive measurements (Figure 1). Image:Summary/Conclusion: We believe that depending on the condition of the buccal epithelium and the technique of taking a swab from patients after HSCT, lymphocytes of donor origin may contaminate the sample. Therefore, the usage of buccal epithelium swab as the only reference material for the recipient STR profile or for confirming the germinal nature of mutations should be avoided in patients after HSCT.
Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia
Authors: Cheng Zhang, Jiaping He, Li Liu, Jishi Wang, Sanbin Wang, Ligen Liu, Jian Ge, Lei Gao, Li Gao, Peiyan Kong, Yao Liu, Jia Liu, Yu Han, Yongliang Zhang, Zhe Sun, Xun Ye, Wenjie Yin, Martina Sersch, Lianjun Shen, Wei William Cao, Xi Zhang
Journal: Blood Cancer Journal (2022)

Abstract Chimeric antigen receptor-engineered T (CAR-T) cells have shown promising efficacy in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, challenges remain including long manufacturing processes that need to be overcome. We presented the CD19-targeting CAR-T cell product GC007F manufactured next-day (FasTCAR-T cells) and administered to patients with R/R B-ALL. A total of 21 patients over 14 years of age with CD19 + R/R B-ALL were screened, enrolled and infused with a single infusion of GC007F CAR-T at three different dose levels. The primary objective of the study was to assess safety, secondary objectives included pharmacokinetics of GC007F cells in patients with R/R B-ALL and preliminary efficacy. We were able to demonstrate in preclinical studies that GC007F cells exhibited better proliferation and tumor killing than conventional CAR-T (C-CAR-T) cells. In this investigator-initiated study all 18 efficacy-evaluable patients achieved a complete remission (CR) (18/18, 100.00%) by day 28, with 17 of the patients (94.4%) achieving CR with minimal residual disease (MRD) negative. Fifteen (83.3%) remained disease free at the 3-month assessment, 14 patients (77.8%) maintaining MRD negative at month 3. Among all 21 enrolled patients, the median peak of CAR-T cell was on day 10, with a median peak copy number of 104899.5/µg DNA and a median persistence period of 56 days (range: 7–327 days). The incidence of cytokine release syndrome (CRS) was 95.2% ( n = 20), with severe CRS occurring in 52.4% ( n = 11) of the patients. Six patients (28.6%) developed neurotoxicity of any grade. GC007F demonstrated superior expansion capacity and a less exhausted phenotype as compared to (C-CAR-T) cells. Moreover, this first-in-human clinical study showed that the novel, next-day manufacturing FasTCAR-T cells was feasible with a manageable toxicity profile in patients with R/R B-ALL.
PB2149: ZANUBRUTINIB IN COMBINATION WITH LENALIDOMIDE AND RITUXIMAB VERSUS R-MINICHOP IN UNFIT OR FRAIL PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA AGED OVER OR EQUAL TO 70 YEARS
Authors: P. Xu, Z. Shi, L. Wang, S. Cheng, W. Zhao
Journal: HemaSphere (2022)

Background: The optimal treatment for elderly diffuse large B-cell lymphoma (DLBCL) patients needs to be further explored due to their comorbidities, intolerability of standard immunochemotherapy, and unfavorable genetic features. The balance of efficacy and safety is a major issue in the treatment of elderly patients. Rituximab in combination with attenuated CHOP (R-miniCHOP) is the standard treatment for unfit or frail elderly patients. However, the toxicity of chemotherapeutic drugs is still inevitable. In a phase 2 trial (NCT04460248), 40 patients aged 75 years or older with newly diagnosed DLBCL received zanubrutinib in combination with lenalidomide and rituximab (ZR2) regimen, and achieved similar treatment response rate as those of attenuated immunochemotherapy (manuscript in preparation). The promising preliminary results of ZR2 make the combination a potentially chemo-free option versus immunochemotherapy in unfit or frail elderly patients. Aims: PEARL study (NCT05179733) is a multicenter, prospective, randomized, open-label, controlled, non-inferiority trial to evaluate the efficacy and safety of ZR2 versus R-miniCHOP in the treatment of unfit or frail newly diagnosed DLBCL patients aged older than or equal to 70 years. Methods: Key eligibility criteria include patients aged ≥ 80 or 70-79 years with comprehensive geriatric assessment stratified as unfit or frail, histologically-confirmed DLBCL without central nervous system involvement, Eastern Cooperative Oncology Group performance status 0-3, and at least one measurable site of disease. Two hundred and eighty patients will be randomized 1:1 to receive either ZR2 or R-miniCHOP for 6 cycles. The primary endpoint is progression-free survival. Secondary endpoints include complete response rate, overall survival, safety, and quality of life. Response will be evaluated before treatment and repeated after 3 cycles and at the end of treatment. Disease response will be assessed by investigator according to Lugano 2014 criteria. Patients’ enrollment is ongoing. Results: N/A Summary/Conclusion: N/A